The present invention relates to asthma therapy.
Bronchial asthma in mammals is characterized by inflammation of the airways, exaggerated airway reactivity to bronchoconstrictor agonists, and attenuated beta-adrenoceptor-mediated airway relaxation (Bai, 1990 Am. Rev. Respir. Dis. 141:552-557; Goldie et al., 1986, Br. J. Clin. Pharmacol. 22:669-676; McFadden et al., 1994, Am. J. Respir. Crit. Care Med. 150:523-526). In humans with atopic asthma, mast cell activation has been implicated in mediating the immediate bronchoconstrictor response which acutely follows antigen inhalation. This response is a process which involves IgE-mediated activation of the high affinity IgE receptor (Fcxcex5RI), leading to cellular degranulation and the release of various mast cell-derived mediators including histamine, eicosanoids, and specific cytokines (Metzger, 1992, Immunol. Rev. 125:37-48; Beaven et al., 1993, Immunol. Today 14:222-226; Galli, 1993, N. Engl. J. Med. 328:257-265). The identification of Fc receptors on other cell types in the lung (e.g., mononuclear cells, eosinophils, and dendritic cells) suggests that, apart from mast cells per se, these other cell types may also serve to propagate the pro-inflammatory allergic pulmonary response, most likely via the orchestrated extended release of various cytokines (Walker et al., 1992, Am. Rev. Respir. Dis. 146:109-115; Watson et al., 1993, Am. J. Respir. Cell Mol. Biol. 8:365-369; Capron et al., 1984, J. Immunol. 132:462-468; Beasley et al., 1989, Am. Rev. Respir. Dis. 139:806-817; Litchfield et al., 1992, J. Asthma 29:181-191; Barnes et al., 1988, Pharmacol. Rev. 40:49-84; Borish et al., 1991, J. Immunol. 146:63-67. It is believed that immune complex/Fc receptor interactions expressed by these cells, i.e., mononuclear cells, eosinophils, and dendritic cells, potentially underlie the progression of the airway inflammatory and bronchoconstrictor responses in asthma, wherein the immediate bronchoconstriction accompanying antigen exposure is followed by the development of the late phase asthmatic response involving various proinflammatory cells. Indeed, recent studies have demonstrated that expression of the inducible form of the low affinity IgE receptor (Fcxcex5RII or CD23) is upregulated on monocytes and alveolar macrophages (Williams et al., 1992, J. Immunol.149:2823-2829), as well as on circulating B lymphocytes (Gagro et al., 1993, Int. Arch. Allergy Immunol. 101:203-208; Rabatic et al., 1993, Exp. Immunol. 94:337-340) isolated from atopic asthmatic subjects. Similarly, exposure of asthmatic subjects to allergen and treatment of isolated monocytes with specific cytokines have been shown to up-regulate Fcxcex5RII expression on mononuclear phagocytes (Williams et al., 1992, J. Immunol. 149:2823-2829; Joseph et al., 1983, J. Clin. Invest. 71:221-230). These findings suggest that altered Fc receptor expression and action in some cell types may contribute to the overall pro-inflammatory asthmatic response. While it is known that exposure of isolated rabbit and human airway smooth muscle (ASM) to atopic asthmatic serum induces the autocrine release and action of specific cytokines (notably IL-1xcex2) by the sensitized ASM cells (Hakonarson et al., 1997, J. Clin. Invest. 99:117-124), the mechanism by which this sensitization is mediated has not been disclosed.
Current treatment options for asthma include medications that control the airway inflammatory component of the disease, e.g., primarily corticosteroids, sodium cromolyn, methylxanthines, leukotriene modifiers) and rapid relief medications that counteract bronchospasm, e.g., primarily beta-adrenergic agents. There are several disadvantages to using these medications as follows. There is a potential lack of effective sustained action; there are side effects associated with prolonged use of these medications, particularly in the case of corticosteroids and beta-adrenergic agents; there is a progressive loss of sensitivity to these treatments after prolonged use; there is limited efficacy of any of these agents in severe cases of asthma; these agents are non-selective, i.e., they do not specifically target the lung, therefore, side-effects affecting other organs are a potential risk. Furthermore, there are data which document an increased risk of dying from bronchial asthma following prolonged treatment of asthma using long-acting beta-adrenergic agents such as fenoterol (Pearce et al., 1990, Thorax 45:170-175; Spitzer et al., 1992, N. Engl. J. Med. 326:560-561).
Approximately fifteen million individuals in the U.S. have asthma and the disease is the cause of more than five thousand deaths annually in the U.S. In children, asthma represents the most prevalent chronic disease, requiring the most frequent use of emergency room visits and hospitalizations. The overall annual cost for asthma care in the U.S. is estimated to be in the range of billions of dollars. Asthma is the most common cause of school and work absenteeism in the U.S.
There is thus a long felt need for additional and more specific and effective compositions and methods for treatment of asthma which additional compositions and methods overcome the deficiencies of the prior art compositions and methods.
The invention relates to a method of preventing induction of an asthmatic state in a human patient comprising administering to the human an anti-Fcxcex5RII receptor protein ligand suspended in a pharmaceutically acceptable carrier in an amount sufficient to inhibit binding of IgE to an Fcxcex5RII receptor protein thereby preventing induction of the asthmatic state in the human. Preferably, the pharmaceutically acceptable carrier is physiological saline.
In one aspect, the ligand is selected from the group consisting of an isolated protein, an isolated polypeptide and a non-peptide.
In a preferred embodiment, the ligand is selected from the group consisting of a polyclonal antibody, a monoclonal antibody, a synthetic antibody, a chimeric antibody and a humanized antibody. Preferably, the anti-Fcxcex5RII receptor protein ligand is an anti-Fcxcex5RII receptor protein antibody.
In another aspect, the ligand is administered to the human in the form of an isolated DNA encoding and capable of expressing the ligand. The DNA may be formulated in a viral or a non-viral vector. When the DNA is formulated in a viral vector, the viral vector is selected from the group consisting of a recombinant vaccinia virus, a recombinant adenovirus, a recombinant retrovirus, a recombinant adeno-associated virus and a recombinant avian pox virus. When the DNA is formulated in a non-viral vector, the non-viral vector is selected from the group consisting of a liposome and a polyamine conjugated DNA.
In yet another aspect, the anti-Fcxcex5RII receptor protein ligand is administered to the human in an amount between about 1 ng/kg and about 100 mg/kg of patient body weight.
The invention also relates to a method of treating asthma in a human patient comprising administering to the human an anti-Fcxcex5RII receptor protein ligand suspended in a pharmaceutically acceptable carrier in an amount sufficient to inhibit binding of IgE to an Fcxcex5RII receptor protein thereby treating asthma in the human. Preferably, the pharmaceutically acceptable carrier is physiological saline.
In one aspect, the ligand is selected from the group consisting of an isolated protein, an isolated polypeptide and a non-peptide.
In a preferred embodiment, the ligand is selected from the group consisting of a polyclonal antibody, a monoclonal antibody, a synthetic antibody, a chimeric antibody and a humanized antibody. Preferably, the anti-Fcxcex5RII receptor protein ligand is an anti-Fcxcex5RII receptor protein antibody.
In another aspect, the ligand is administered to the human in the form of an isolated DNA encoding and capable of expressing the ligand. The DNA may be formulated in a viral or a non-viral vector. When the DNA is formulated in a viral vector, the viral vector is selected from the group consisting of a recombinant vaccinia virus, a recombinant adenovirus, a recombinant retrovirus, a recombinant adeno-associated virus and a recombinant avian pox virus. When the DNA is formulated in a non-viral vector, the non-viral vector is selected from the group consisting of a liposome and a polyamine conjugated DNA.
In yet another aspect, the anti-Fcxcex5RII receptor protein ligand is administered to the human in an amount between about 1 ng/kg and about 100 mg/kg of patient body weight.
Also included in the invention is a method of treating a human having asthma comprising administering to the human a pharmaceutically effective amount of an isolated nucleic acid encoding an anti-Fcxcex5RII receptor protein ligand, wherein the nucleic acid expresses the ligand in vivo in an amount sufficient to treat the asthma.
In addition, the invention includes a method of identifying an anti-Fcxcex5RII receptor protein ligand comprising providing a mixture comprising IgE and a population of cells which express an Fcxcex5RII receptor protein, incubating the mixture in the presence or absence of a test ligand, and measuring the level of IgE bound to the Fcxcex5RII receptor protein, wherein a lower level of IgE bound to the cells in the presence of the test compound compared with the level of binding of IgE to the cells in the absence of the test compound is an indication that the test compound is an anti-Fcxcex5RII receptor protein ligand.
In a preferred embodiment of this aspect of the invention, the cells are airway smooth muscle cells.
The invention also includes a ligand useful for inhibiting binding of IgE to an Fcxcex5RII receptor protein identified by a method comprising providing a mixture comprising IgE and a population of cells which express an Fcxcex5RII receptor protein, incubating the mixture in the presence or absence of a test ligand, and measuring the level of IgE bound to the Fcxcex5RII receptor protein, wherein a lower level of IgE bound to the cells in the presence of the test compound compared with the level of binding of IgE to the cells in the absence of the test compound is an indication that the test compound is an anti-Fcxcex5RII receptor protein ligand.
In addition, the invention includes a method of inhibiting binding of IgE to an Fcxcex5RII receptor protein expressed on a cell comprising administering to the cell an anti-Fcxcex5RII receptor protein ligand.
The invention also includes a method of regulating production of interleukin-1xcex2 in a cell. The method comprises contacting a cell with an anti-Fcxcex5RII receptor protein ligand in an amount sufficient to inhibit binding of IgE to an anti-Fcxcex5RII receptor protein thereby regulating production of interleukin-1xcex2 in a cell.